Recognize Yourself—Innate Sensing of Non-LTR Retrotransposons

Figures

• 

  Figure 1. Types of retrotransposons in humans. Non-long terminal repeat (LTR) retroelements include long interspersed element (LINE)-1 elements, Alu elements, and short-interspersed element (SINE)-variable tandem repeats (VNTR)-Alu (SVA) elements. Full-length LINE-1 elements are approximately 6 kb in length and encode two open-reading frames (ORF1 and ORF2) in sense orientation, flanked by untranslated regions (UTR). LINE-1 also contains an antisense open reading frame (ORF0) within the 5′UTR, in which the internal promoter is located. The 3′UTR includes a poly(A) signal. The 300 bp Alu elements are composed of a left and right monomer separated by an adenosine-rich sequence (A-rich). The left monomer contains an internal RNA polymerase III promoter (A and B boxes). The structure of SVA elements starts with a (CCCTCT)n hexamer repeat region, which is followed by an Alu-like domain, a variable tandem repeats (VNTR) region, a human endogenous retrovirus (HERV)-K-derived SINE-R domain, and a poly(A) signal. LTR retrotransposons mainly include HERVs. HERV sequences consist of two LTRs flanking four open reading frames, coding for structural proteins (gag), protease (pro), polymerase and…

• 

  Figure 2. Sensing of LINE1 and Alu elements. Here, we give an overview of the different nucleic acids of LINE-1 and Alu elements and how they can be sensed by pattern recognition receptors (PRRs, yellow boxes) during retrotransposition. In the nucleus, LINE-1 and Alu sequences are transcribed by RNA polymerase II (LINE-1/Alu) or III (Alu), resulting in single-stranded RNA molecules (ssRNA). Upon export to the cytoplasm, ssRNAs of both elements have been shown to activate double-stranded RNA (dsRNA) sensors, such as melanoma differentiation-associated gene 5 (MDA5) or retinoic acid-inducible gene I (RIG-I) under certain conditions. After translation, LINE-1 ribonucleoprotein complexes (RNPs) are formed and are composed of de novo synthesized ORF1p and ORF2p and the RNA molecule they have been translated from. Accumulation of excess RNPs is sensed by human tripartite motif-containing 5α (TRIM5α) in the cytoplasm. RNPs are imported into the nucleus, where the process of target-primed reverse transcription (TPRT) takes place to allow integration of LINE-1 at a new genomic location. During this process, genomic DNA is cleaved by ORF2p, liberating a 3′OH group, which is used to initiate reverse…